Little progress has been made in the prevention and treatment of metastatic breast cancer, the primary cause of cancer related deaths. Bone is the most common and often only site of breast cancer metastasis. Thus, there is significant need for new and innovative bone targeted therapies. The role of the microenvironment in facilitating tumor growth is well established yet few targeted therapies are available. Nanoparticles (NPs) represent a new technology for targeted drug delivery to the tumor and tumor supportive cells of the microenvironment. Our long-term goal is to develop novel NP therapies that target both tumor cells and host cells for the treatment of bone metastases. We have developed novel targeted micelle (20nm) NPs that will better exit the tumor vasculature. Our NPs have a novel drug delivery method to deliver drug directly to the cell cytoplasm, increasing intracellular drug concentrations. Specific targeting is critical to the effectiveness of these NPs. We will use a RGD peptidomimetic to target activated v3 integrin. v3 becomes activated and is highly expressed in poor-prognosis breast cancers and on tumor supportive host cells of the tumor microenvironment particularly in bone (bone destroying osteoclasts, tumor induced blood vessels, and protumor myeloid cells). We hypothesize that activated v3 integrin targeted NPs will deliver drug to both tumor and tumor supportive cells of the bone microenvironment. We have proposed the following specific aims: 1) Do v3 targeted nanoparticles bind both tumor and host cell types at levels sufficient to produce inhibitory effects on the target cell? We will assess binding and functional effects of NP drug delivery to v3 expressing murine and patient tumor lines and myeloid lineage cells. We will assay for changes in viability, adhesion and bone resorption. 2) What cell types of the bone metastatic niche are targeted by v3 directed nanoparticles in early and late stage tumors? NP binding depends on the availability of cell types and level of v3 expression and activation. We will assess binding to tumor cells, osteoclasts and tumor associated macrophages (TAMs) and endothelial cells. 3) What is the therapeutic potential of v3 integrin targeted nanoparticle technologies for the treatment of bone metastases? We will evaluate effects on bone tumor growth and progression after treatment with v3 NPs loaded with traditional chemotherapy,docetaxel, and/or v3 NPs loaded with the bone and stromal targeted drug, zoledronic acid. We will use both orthotopic primary breast cancer models that metastasize to the bone and intracardiac metastasis models to determine effects on metastasis prevention and on established bone metastases. Nanoparticle localization and specific effects on tumor cell apoptosis, blood vessel number, osteoclast number, bone loss and changes in TAM populations will be assessed. This research project is relevant to the mission of the NCI through the development of novel therapies for the treatment and prevention of metastatic breast cancer.